Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system white matter of humans and is believed to be of autoimmune etiology. The disease is characterized by prominent T-cell and macrophage infiltrates, demyelination and neurological dysfunction. Myelin basic protein (MBP) has been extensively studied as a potential autoantigen in the disease because of its role as an inducing agent in the major animal model of MS, experimental allergic encephalomyelitis (EAE), as well as its role in the human disease post viral encephalomyelitis.
A major hypothesis regarding the pathogenesis of MS is that T-cells reactive with myelin basic protein in the white matter of the CNS initiate the inflammatory process. The demonstration that activated T-cells specific for myelin basic protein (MBP) can be isolated from MS patients (Allegretta, M., et al., Science: 247: 778, 1990) implicates MBP-reactive T-cells in the pathogenesis of the disease.
Experimental allergic encephalomyelitis (EAE) is the primary animal model for MS. EAE can readily be induced in small mammals by immunization with myelin basic protein (MBP) in an appropriate adjuvant or by passive transfer of CD4+, MBP-reactive T-cells (Alvord Jr, E. C., et al. eds. in Experimental Allergic Encephalomyelitis: A Useful Model for Multiple Sclerosis, A. R. Liss, N.Y., 1984; Makhtarian, D. E., et al. Nature 309: 356, 1984; Ben-Nun, A. et al. J. Immunol. 129:303, 1982). The T-cells that induce EAE in both mice and rats recognize specifically peptides corresponding to species-specific immunodominant regions of MBP presented on antigen-presenting cells by unique Major Histocompatibility Complex (MHC) class II molecules.
T-cell receptors are composed of two distinct chains of protein material. Certain T-cell receptors (TCRs), composed of V-beta (VB) chains and V-alpha (VA) chains, are known to recognize MBP. In SJL/PL mice, encephalitogenic (i.e., disease-inducing when administered to mice) T-cells having these receptors recognize an N-terminal mouse MBP peptide (residues 1-9) presented by an MHC molecule (Zamvil, S. S. et al., Nature 324: 258, 1986) encoded by the mouse gene H-2. The majority of T-cell receptors recognizing this peptide presented in connection with the MHC are encoded by the mouse TCR genes VB8.2 and VA2 or VA4. In Lewis rats, TCR gene segments that are homologous with the mouse VB8.2 and TCR VA2 genes have been found in encephalitogenic T-cells which recognize MBP residues 68-88 in the context of the Lewis rat MHC (Burns, F. R., et al., J. Exp. Med. 169: 27, 1989). Administration of a VB8.2-specific monoclonal antibody (i.e., an antibody recognizing the product VB8.2 expressed by the corresponding gene) to mice has been shown to be effective in treating murine EAE. Immunization with peptides specifically corresponding to the TCR VB8.2 amino acid sequence ameliorates EAE in the Lewis rat (Vanderbark, A. A., et al., Nature 341: 541-544, 1989; Howell, M. D. et al., Science: 246, 668; 1989). However, the regions of an autoantigen (such as MBP) that behave as immunodominant regions are species specific. It has not heretofore been determined if common V-gene usage in TCR V-genes exists in humans among T-cells recognizing immunodominant regions of MBP nor have these immunodominant regions been positively identified in MS patients.
The current treatments for MS involve administration of drugs which act in a non-specific fashion to suppress the immune response in the subject. Examples of such drugs are cyclophosphamide, Imuran (azathioprine) and the cyclosporin A. Steroid compounds such as prednisone and methylprednisolone are also employed in many instances. These drugs have limited efficacy against MS. Use of such drugs is limited by toxicity and by the fact that they induce "global" immunosuppression upon prolonged treatment, i.e., they down regulate the normal protective immune response to pathogenic microorganisms thereby increasing the risk of infection. A further drawback is the increased risk that malignancies will develop in patients receiving prolonged global immunosuppression.
Other therapies are being developed for the treatment of autoimmune diseases in general and MS in particular. U.S. patent application Ser. No. 65,794 filed Jun. 24, 1987 (now abandoned) and copending International Patent Application PCT/US88/02139, filed Jun. 24, 1988, disclose that oral or enteral administration of myelin basic protein and of disease inducing and non-inducing fragments and analogs thereof is effective in suppressing acute monophasic EAE and are useful in suppressing MS symptoms when similarly administered.
U.S. patent application Ser. No. 454,806 filed Dec. 20, 1989, now abandoned, discloses the aerosol administration of autoantigens, disease-suppressive fragments of said autoantigens and analogs thereof as an effective treatment for treating T-cell mediated autoimmune diseases such as MS.
A U.S. patent application filed Mar. 3, 1990 entitled "Enhancement of the Down Regulation of Autoimmune Diseases by Oral Administration of Autoantigens" discloses synergists (enhancers) for use with oral administration of autoantigens, disease-suppressive fragments and analogs thereof as effective treatments for T-cell mediated autoimmune diseases.
In furtherance of the efforts and goals expressed in these prior applications, i.e., the design of effective, specific therapeutic treatments for MS, what is needed in the art is to determine if common V-gene usage associated with Major Histocompatibility Complex antigens exists in humans suffering from MS. In other words, there is a need to determine whether encephalitogenic T-cells isolated from human MS victims use restricted TCR VB genes as observed in rodents and whether this function can be exploited to combat disease symptoms. In addition, it is necessary to determine the major immunodominant epitope domain present on human MBP, again with a view towards exploiting all or part of such domain towards therapeutic ends.
It is an object of the present invention to provide agents and methods based upon the human TCR for treating humans suffering from autoimmune diseases having the symptoms of MS.
Another object of the present invention is to provide compositions and pharmaceutical formulations useful for treating humans suffering from autoimmune diseases having the symptoms of MS.
A still further object of the invention is to provide compositions and pharmaceutical formulations useful for administration to humans for the purpose of preventing or attenuating to the manifestation (i.e., clinical symptoms) of autoimmune diseases having the symptoms of MS. Another object of this invention is to provide reagents useful in diagnosis of MS (or of another disease presenting with the same symptoms). (For example TCR-based peptides or peptides based on the immunodominant domain of the human MBP can constitute such diagnostic reagents.)
These and other objects of the present invention will be apparent to those of ordinary skill in the art in light of the present specification, drawings and claims.